Patent EP 21121 describes 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines which are active in central nervous system disorders such as psychiatric and neurological disorders, and are particularly useful as anticonvulsants, for example in the treatment of epilepsy. Of these, the preferred compound is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, of formula (I):

This compound is commonly known as lamotrigine and is marketed as an anti-epileptic drug.
The said European patent discloses the preparation of lamotrigine by the reaction of 2,3-dichlorobenzoyl cyanide with aminoguanidine bicarbonate to give the intermediate 2-(2,3-dichlorophenyl)-2-(aminoguanidine)acetonitrile, of formula (II):
which by cyclisation, in an aliphatic alcohol under reflux in the presence of a strong base, yields lamotrigine.
The preparation of the intermediate of formula (II) by reaction of 2,3-dichlorobenzoyl cyanide with aminoguanidine bicarbonate is carried out in said patent EP 21121 in an aqueous solution of nitric acid in the presence of dimethyl sulphoxide. Subsequently, patents EP 247892, EP 963980 and WO 0035888 described the same reaction for preparing the intermediate of formula (II), but in this case in an aqueous solution of sulphuric acid and with acetonitrile as solvent.
The method described for preparing said intermediate nevertheless has disadvantages of an environmental type, since it uses solvents such as dimethyl sulphoxide and acetonitrile, and of an economic type due to it being an excessively slow reaction. In the aqueous medium in which the reaction is carried out and under the conditions described in that method, the 2,3-dichlorobenzoyl cyanide has a tendency to hydrolyse and its reaction with aminoguanidine bicarbonate is too slow, requiring 2 to 7 days, after which time the yield obtained is only 15% to 60%.
European patent application EP 1127873 has the object of improving said method for preparing the intermediate by carrying out the reaction in a non-aqueous medium using polyphosphoric acid and with acetonitrile as solvent. However, this method still presents the same environmental disadvantages, since it also uses toxic solvents, as well as economic disadvantages in that, although the reaction time has been reduced to approximately 20 h, the reaction remains slow.
International patent application WO 0149669 describes the same reaction for preparing the intermediate of formula (II) using 2,3-dichlorobenzoyl cyanide and aminoguanidine bicarbonate, but in this case in the presence of concentrated sulphuric acid and p-toluenesulphonic acid in toluene at 80° C. Although under such conditions a reduced reaction time is achieved, it is nevertheless necessary to employ high temperatures, with the disadvantages this entails, such as the formation of decomposition or degradation by-products. Moreover, this method still has disadvantages of an economic type, since the yields obtained are of the order of 50%.
Furthermore, in the methods described above for preparing the intermediate, once the reaction has finished the acid suspension is filtered directly, without taking into account the traces of hydrogen cyanide produced as a reaction by-product.
The preparation of lamotrigine by cyclisation of the intermediate of formula (II), as noted above, was initially disclosed in patent EP 21121, refluxing in an alcohol in the presence of a strong base. This cyclisation reaction was subsequently disclosed in aliphatic alcohol under reflux in the absence of a base in the following European patents: EP 247892, EP 963980, EP 1127873. However, in order to prepare an end product of high purity, patents EP 963980, WO 0035888 and WO 0149669 disclosed that following such cyclisation one or more steps of recrystallisation are required, with the disadvantages this involves, such as yield losses, following which disclosed purities of only 99.1%, or at best 99.7%, are achieved.
Due to all this, and taking account of the prior art described, it is still necessary provide a method for preparing the intermediate of formula (II) and, therefore, of preparing lamotrigine, which is fast, cheap, safe and offers good yields.